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PLoS Genetics

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https://www.readbyqxmd.com/read/28820880/knock-out-of-a-mitochondrial-sirtuin-protects-neurons-from-degeneration-in-caenorhabditis-elegans
#1
Rachele Sangaletti, Massimo D'Amico, Jeff Grant, David Della-Morte, Laura Bianchi
Sirtuins are NAD⁺-dependent deacetylases, lipoamidases, and ADP-ribosyltransferases that link cellular metabolism to multiple intracellular pathways that influence processes as diverse as cell survival, longevity, and cancer growth. Sirtuins influence the extent of neuronal death in stroke. However, different sirtuins appear to have opposite roles in neuronal protection. In Caenorhabditis elegans, we found that knock-out of mitochondrial sirtuin sir-2.3, homologous to mammalian SIRT4, is protective in both chemical ischemia and hyperactive channel induced necrosis...
August 18, 2017: PLoS Genetics
https://www.readbyqxmd.com/read/28817564/cell-cycle-related-kinase-ccrk-regulates-ciliogenesis-and-hedgehog-signaling-in-mice
#2
Ashley Snouffer, Desmond Brown, Hankyu Lee, Jonathon Walsh, Floria Lupu, Ryan Norman, Karl Lechtreck, Hyuk Wan Ko, Jonathan Eggenschwiler
The Hedgehog (Hh) signaling pathway plays a key role in cell fate specification, proliferation, and survival during mammalian development. Cells require a small organelle, the primary cilium, to respond properly to Hh signals and the key regulators of Hh signal transduction exhibit dynamic localization to this organelle when the pathway is activated. Here, we investigate the role of Cell Cycle Related kinase (CCRK) in regulation of cilium-dependent Hh signaling in the mouse. Mice mutant for Ccrk exhibit a variety of developmental defects indicative of inappropriate regulation of this pathway...
August 17, 2017: PLoS Genetics
https://www.readbyqxmd.com/read/28806779/a-mutation-in-nischarin-causes-otitis-media-via-limk1-and-nf-%C3%AE%C2%BAb-pathways
#3
Michael Crompton, Tom Purnell, Hayley E Tyrer, Andrew Parker, Greg Ball, Rachel E Hardisty-Hughes, Richard Gale, Debbie Williams, Charlotte H Dean, Michelle M Simon, Ann-Marie Mallon, Sara Wells, Mahmood F Bhutta, Martin J Burton, Hilda Tateossian, Steve D M Brown
Otitis media (OM), inflammation of the middle ear (ME), is a common cause of conductive hearing impairment. Despite the importance of the disease, the aetiology of chronic and recurrent forms of middle ear inflammatory disease remains poorly understood. Studies of the human population suggest that there is a significant genetic component predisposing to the development of chronic OM, although the underlying genes are largely unknown. Using N-ethyl-N-nitrosourea mutagenesis we identified a recessive mouse mutant, edison, that spontaneously develops a conductive hearing loss due to chronic OM...
August 14, 2017: PLoS Genetics
https://www.readbyqxmd.com/read/28806777/a-synthetic-sickness-screen-for-senescence-re-engagement-targets-in-mutant-cancer-backgrounds
#4
Claire J Cairney, Lauren S Godwin, Alan E Bilsland, Sharon Burns, Katrina H Stevenson, Lynn McGarry, John Revie, Jon D Moore, Ceri M Wiggins, Rebecca S Collinson, Clare Mudd, Elpida Tsonou, Mahito Sadaie, Dorothy C Bennett, Masashi Narita, Christopher J Torrance, W Nicol Keith
Senescence is a universal barrier to immortalisation and tumorigenesis. As such, interest in the use of senescence-induction in a therapeutic context has been gaining momentum in the past few years; however, senescence and immortalisation remain underserved areas for drug discovery owing to a lack of robust senescence inducing agents and an incomplete understanding of the signalling events underlying this complex process. In order to address this issue we undertook a large-scale morphological siRNA screen for inducers of senescence phenotypes in the human melanoma cell line A375P...
August 14, 2017: PLoS Genetics
https://www.readbyqxmd.com/read/28806765/pka-activity-is-essential-for-relieving-the-suppression-of-hyphal-growth-and-appressorium-formation-by-mosfl1-in-magnaporthe-oryzae
#5
Yang Li, Xue Zhang, Shuai Hu, Huiquan Liu, Jin-Rong Xu
In the rice blast fungus Magnaporthe oryzae, the cAMP-PKA pathway regulates surface recognition, appressorium turgor generation, and invasive growth. However, deletion of CPKA failed to block appressorium formation and responses to exogenous cAMP. In this study, we generated and characterized the cpk2 and cpkA cpk2 mutants and spontaneous suppressors of cpkA cpk2 in M. oryzae. Our results demonstrate that CPKA and CPK2 have specific and overlapping functions, and PKA activity is essential for appressorium formation and plant infection...
August 14, 2017: PLoS Genetics
https://www.readbyqxmd.com/read/28806762/a-becn1-mutation-mediates-hyperactive-autophagic-sequestration-of-amyloid-oligomers-and-improved-cognition-in-alzheimer-s-disease
#6
Altea Rocchi, Soh Yamamoto, Tabitha Ting, Yuying Fan, Katherine Sadleir, Yigang Wang, Weiran Zhang, Sui Huang, Beth Levine, Robert Vassar, Congcong He
Impairment of the autophagy pathway has been observed during the pathogenesis of Alzheimer's disease (AD), a neurodegenerative disorder characterized by abnormal deposition of extracellular and intracellular amyloid β (Aβ) peptides. Yet the role of autophagy in Aβ production and AD progression is complex. To study whether increased basal autophagy plays a beneficial role in Aβ clearance and cognitive improvement, we developed a novel genetic model to hyperactivate autophagy in vivo. We found that knock-in of a point mutation F121A in the essential autophagy gene Beclin 1/Becn1 in mice significantly reduces the interaction of BECN1 with its inhibitor BCL2, and thus leads to constitutively active autophagy even under non-autophagy-inducing conditions in multiple tissues, including brain...
August 14, 2017: PLoS Genetics
https://www.readbyqxmd.com/read/28806749/defining-the-genetic-susceptibility-to-cervical-neoplasia-a-genome-wide-association-study
#7
Paul J Leo, Margaret M Madeleine, Sophia Wang, Stephen M Schwartz, Felicity Newell, Ulrika Kymmer, Kari Hemminki, Goran Hallmans, Sven Tiews, Winfried Steinberg, Janet S Rader, Felipe Castro, Mahboobeh Safaeian, Eduardo L Franco, François Coutlée, Claes Ohlsson, Adrian Cortes, Mhairi Marshall, Pamela Mukhopadhyay, Katie Cremin, Lisa G Johnson, Suzanne Garland, Sepehr N Tabrizi, Nicolas Wentzensen, Freddy Sitas, Julian Little, Maggie Cruickshank, Ian H Frazer, Allan Hildesheim, Matthew A Brown
A small percentage of women with cervical HPV infection progress to cervical neoplasia, and the risk factors determining progression are incompletely understood. We sought to define the genetic loci involved in cervical neoplasia and to assess its heritability using unbiased unrelated case/control statistical approaches. We demonstrated strong association of cervical neoplasia with risk and protective HLA haplotypes that are determined by the amino-acids carried at positions 13 and 71 in pocket 4 of HLA-DRB1 and position 156 in HLA-B...
August 14, 2017: PLoS Genetics
https://www.readbyqxmd.com/read/28806732/loss-of-the-chromatin-modifier-kdm2aa-causes-brafv600e-independent-spontaneous-melanoma-in-zebrafish
#8
Catherine M Scahill, Zsofia Digby, Ian M Sealy, Sonia Wojciechowska, Richard J White, John E Collins, Derek L Stemple, Till Bartke, Marie E Mathers, E Elizabeth Patton, Elisabeth M Busch-Nentwich
KDM2A is a histone demethylase associated with transcriptional silencing, however very little is known about its in vivo role in development and disease. Here we demonstrate that loss of the orthologue kdm2aa in zebrafish causes widespread transcriptional disruption and leads to spontaneous melanomas at a high frequency. Fish homozygous for two independent premature stop codon alleles show reduced growth and survival, a strong male sex bias, and homozygous females exhibit a progressive oogenesis defect. kdm2aa mutant fish also develop melanomas from early adulthood onwards which are independent from mutations in braf and other common oncogenes and tumour suppressors as revealed by deep whole exome sequencing...
August 14, 2017: PLoS Genetics
https://www.readbyqxmd.com/read/28806726/replication-fork-slowing-and-stalling-are-distinct-checkpoint-independent-consequences-of-replicating-damaged-dna
#9
Divya Ramalingam Iyer, Nicholas Rhind
In response to DNA damage during S phase, cells slow DNA replication. This slowing is orchestrated by the intra-S checkpoint and involves inhibition of origin firing and reduction of replication fork speed. Slowing of replication allows for tolerance of DNA damage and suppresses genomic instability. Although the mechanisms of origin inhibition by the intra-S checkpoint are understood, major questions remain about how the checkpoint regulates replication forks: Does the checkpoint regulate the rate of fork progression? Does the checkpoint affect all forks, or only those encountering damage? Does the checkpoint facilitate the replication of polymerase-blocking lesions? To address these questions, we have analyzed the checkpoint in the fission yeast Schizosaccharomyces pombe using a single-molecule DNA combing assay, which allows us to unambiguously separate the contribution of origin and fork regulation towards replication slowing, and allows us to investigate the behavior of individual forks...
August 14, 2017: PLoS Genetics
https://www.readbyqxmd.com/read/28797033/a-shh-foxf1-bmp4-signaling-axis-regulating-growth-and-differentiation-of-epithelial-and-mesenchymal-tissues-in-ureter-development
#10
Tobias Bohnenpoll, Anna B Wittern, Tamrat M Mamo, Anna-Carina Weiss, Carsten Rudat, Marc-Jens Kleppa, Karin Schuster-Gossler, Irina Wojahn, Timo H-W Lüdtke, Mark-Oliver Trowe, Andreas Kispert
The differentiated cell types of the epithelial and mesenchymal tissue compartments of the mature ureter of the mouse arise in a precise temporal and spatial sequence from uncommitted precursor cells of the distal ureteric bud epithelium and its surrounding mesenchyme. Previous genetic efforts identified a member of the Hedgehog (HH) family of secreted proteins, Sonic hedgehog (SHH) as a crucial epithelial signal for growth and differentiation of the ureteric mesenchyme. Here, we used conditional loss- and gain-of-function experiments of the unique HH signal transducer Smoothened (SMO) to further characterize the cellular functions and unravel the effector genes of HH signaling in ureter development...
August 10, 2017: PLoS Genetics
https://www.readbyqxmd.com/read/28793313/deciphering-the-genetic-control-of-gene-expression-following-mycobacterium-leprae-antigen-stimulation
#11
Jérémy Manry, Yohann Nédélec, Vinicius M Fava, Aurélie Cobat, Marianna Orlova, Nguyen Van Thuc, Vu Hong Thai, Guillaume Laval, Luis B Barreiro, Erwin Schurr
Leprosy is a human infectious disease caused by Mycobacterium leprae. A strong host genetic contribution to leprosy susceptibility is well established. However, the modulation of the transcriptional response to infection and the mechanism(s) of disease control are poorly understood. To address this gap in knowledge of leprosy pathogenicity, we conducted a genome-wide search for expression quantitative trait loci (eQTL) that are associated with transcript variation before and after stimulation with M. leprae sonicate in whole blood cells...
August 9, 2017: PLoS Genetics
https://www.readbyqxmd.com/read/28793308/genetic-analysis-of-the-candida-albicans-biofilm-transcription-factor-network-using-simple-and-complex-haploinsufficiency
#12
Virginia E Glazier, Thomas Murante, Daniel Murante, Kristy Koselny, Yuan Liu, Dongyeop Kim, Hyun Koo, Damian J Krysan
Biofilm formation by Candida albicans is a key aspect of its pathobiology and is regulated by an integrated network of transcription factors (Bcr1, Brg1, Efg1, Ndt80, Rob1, and Tec1). To understand the details of how the transcription factors function together to regulate biofilm formation, we used a systematic genetic interaction approach based on generating all possible double heterozygous mutants of the network genes and quantitatively analyzing the genetic interactions between them. Overall, the network is highly susceptible to genetic perturbation with the six network heterozygous mutants all showing alterations in biofilm formation (haploinsufficiency)...
August 9, 2017: PLoS Genetics
https://www.readbyqxmd.com/read/28787458/integration-of-the-tricarboxylic-acid-tca-cycle-with-camp-signaling-and-sfl2-pathways-in-the-regulation-of-co2-sensing-and-hyphal-development-in-candida-albicans
#13
Li Tao, Yulong Zhang, Shuru Fan, Clarissa J Nobile, Guobo Guan, Guanghua Huang
Morphological transitions and metabolic regulation are critical for the human fungal pathogen Candida albicans to adapt to the changing host environment. In this study, we generated a library of central metabolic pathway mutants in the tricarboxylic acid (TCA) cycle, and investigated the functional consequences of these gene deletions on C. albicans biology. Inactivation of the TCA cycle impairs the ability of C. albicans to utilize non-fermentable carbon sources and dramatically attenuates cell growth rates under several culture conditions...
August 7, 2017: PLoS Genetics
https://www.readbyqxmd.com/read/28817572/tissue-specific-insulin-signaling-mediates-female-sexual-attractiveness
#14
Tatyana Y Fedina, Devin Arbuthnott, Howard D Rundle, Daniel E L Promislow, Scott D Pletcher
Individuals choose their mates so as to maximize reproductive success, and one important component of this choice is assessment of traits reflecting mate quality. Little is known about why specific traits are used for mate quality assessment nor about how they reflect it. We have previously shown that global manipulation of insulin signaling, a nutrient-sensing pathway governing investment in survival versus reproduction, affects female sexual attractiveness in the fruit fly, Drosophila melanogaster. Here we demonstrate that these effects on attractiveness derive from insulin signaling in the fat body and ovarian follicle cells, whose signals are integrated by pheromone-producing cells called oenocytes...
August 2017: PLoS Genetics
https://www.readbyqxmd.com/read/28817566/inhibition-of-mutagenic-translesion-synthesis-a-possible-strategy-for-improving-chemotherapy
#15
Kinrin Yamanaka, Nimrat Chatterjee, Michael T Hemann, Graham C Walker
No abstract text is available yet for this article.
August 2017: PLoS Genetics
https://www.readbyqxmd.com/read/28817560/fruit-weight-is-controlled-by-cell-size-regulator-encoding-a-novel-protein-that-is-expressed-in-maturing-tomato-fruits
#16
Qi Mu, Zejun Huang, Manohar Chakrabarti, Eudald Illa-Berenguer, Xiaoxi Liu, Yanping Wang, Alexis Ramos, Esther van der Knaap
Increases in fruit weight of cultivated vegetables and fruits accompanied the domestication of these crops. Here we report on the positional cloning of a quantitative trait locus (QTL) controlling fruit weight in tomato. The derived allele of Cell Size Regulator (CSR-D) increases fruit weight predominantly through enlargement of the pericarp areas. The expanded pericarp tissues result from increased mesocarp cell size and not from increased number of cell layers. The effect of CSR on fruit weight and cell size is found across different genetic backgrounds implying a consistent impact of the locus on the trait...
August 2017: PLoS Genetics
https://www.readbyqxmd.com/read/28796803/adaptive-introgression-from-distant-caribbean-islands-contributed-to-the-diversification-of-a-microendemic-adaptive-radiation-of-trophic-specialist-pupfishes
#17
Emilie J Richards, Christopher H Martin
Rapid diversification often involves complex histories of gene flow that leave variable and conflicting signatures of evolutionary relatedness across the genome. Identifying the extent and source of variation in these evolutionary relationships can provide insight into the evolutionary mechanisms involved in rapid radiations. Here we compare the discordant evolutionary relationships associated with species phenotypes across 42 whole genomes from a sympatric adaptive radiation of Cyprinodon pupfishes endemic to San Salvador Island, Bahamas and several outgroup pupfish species in order to understand the rarity of these trophic specialists within the larger radiation of Cyprinodon...
August 2017: PLoS Genetics
https://www.readbyqxmd.com/read/28787446/microrna-275-targets-sarco-endoplasmic-reticulum-ca2-adenosine-triphosphatase-serca-to-control-key-functions-in-the-mosquito-gut
#18
Bo Zhao, Keira J Lucas, Tusar T Saha, Jisu Ha, Lin Ling, Vladimir A Kokoza, Sourav Roy, Alexander S Raikhel
The yellow fever mosquito Aedes aegypti is the major vector of arboviruses, causing numerous devastating human diseases, such as dengue and yellow fevers, Chikungunya and Zika. Female mosquitoes need vertebrate blood for egg development, and repeated cycles of blood feeding are tightly linked to pathogen transmission. The mosquito's posterior midgut (gut) is involved in blood digestion and also serves as an entry point for pathogens. Thus, the mosquito gut is an important tissue to investigate. The miRNA aae-miR-275 (miR-275) has been shown to be required for normal blood digestion in the female mosquito; however, the mechanism of its action has remained unknown...
August 2017: PLoS Genetics
https://www.readbyqxmd.com/read/28787443/rare-coding-variants-pinpoint-genes-that-control-human-hematological-traits
#19
Abdou Mousas, Georgios Ntritsos, Ming-Huei Chen, Ci Song, Jennifer E Huffman, Ioanna Tzoulaki, Paul Elliott, Bruce M Psaty, Paul L Auer, Andrew D Johnson, Evangelos Evangelou, Guillaume Lettre, Alexander P Reiner
The identification of rare coding or splice site variants remains the most straightforward strategy to link genes with human phenotypes. Here, we analyzed the association between 137,086 rare (minor allele frequency (MAF) <1%) coding or splice site variants and 15 hematological traits in up to 308,572 participants. We found 56 such rare coding or splice site variants at P<5x10-8, including 31 that are associated with a blood-cell phenotype for the first time. All but one of these 31 new independent variants map to loci previously implicated in hematopoiesis by genome-wide association studies (GWAS)...
August 2017: PLoS Genetics
https://www.readbyqxmd.com/read/28787442/comparative-transcriptomes-of-adenocarcinomas-and-squamous-cell-carcinomas-reveal-molecular-similarities-that-span-classical-anatomic-boundaries
#20
Eric W Lin, Tatiana A Karakasheva, Dong-Jin Lee, Ju-Seog Lee, Qi Long, Adam J Bass, Kwok K Wong, Anil K Rustgi
Advances in genomics in recent years have provided key insights into defining cancer subtypes "within-a-tissue"-that is, respecting traditional anatomically driven divisions of medicine. However, there remains a dearth of data regarding molecular profiles that are shared across tissues, an understanding of which could lead to the development of highly versatile, broadly applicable therapies. Using data acquired from The Cancer Genome Atlas (TCGA), we performed a transcriptomics-centered analysis on 1494 patient samples, comparing the two major histological subtypes of solid tumors (adenocarcinomas and squamous cell carcinomas) across organs, with a focus on tissues in which both subtypes arise: esophagus, lung, and uterine cervix...
August 2017: PLoS Genetics
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